Asynchronous Involvement of VLPFC and DLPFC During Negative Emotion Processing: An Online Transcranial Magnetic Stimulation Study.

The ventrolateral prefrontal cortex (VLPFC) and dorsolateral prefrontal cortex (DLPFC) have been found to play important roles in negative emotion processing. However, the specific time window of their involvement remains unknown. This study addressed this issue in three experiments using single-pulse transcranial magnetic stimulation (TMS). We found that TMS applied over the VLPFC at 400 ms after negative emotional exposure significantly enhanced negative feelings compared to the vertex condition. Furthermore, TMS applied over the DLPFC at both 0 ms and 600 ms after negative emotional exposure also resulted in deteriorated negative feelings. These findings provide potential evidence for the VLPFC-dependent semantic processing (∼400 ms) and the DLPFC-dependent attentional and cognitive control (∼0/600 ms) in negative emotion processing. The asynchronous involvement of these frontal cortices not only deepens our understanding of the neural mechanisms underlying negative emotion processing but also provides valuable temporal parameters for neurostimulation therapy targeting patients with mood disorders.

Emotion regulation of social pain: double dissociation of lateral prefrontal cortices supporting reappraisal and distraction.

The dorsolateral prefrontal cortex (DLPFC) and ventrolateral prefrontal cortex (VLPFC) are both crucial regions involved in voluntary emotion regulation. However, it remains unclear whether the two regions show functional specificity for reappraisal and distraction. This study employed transcranial magnetic stimulation (TMS) to explore, in a real social interactive scenario, whether different lateral prefrontal regions play relatively specific roles in downregulating social pain via reappraisal and distraction. Participants initially took part in a social interactive game, followed by receiving either active (the DLPFC- or VLPFC-activated group, n = 100 per group) or control (the vertex-activated group, n = 100) TMS session. They were then instructed to use both distraction and reappraisal strategies to downregulate any negative emotions evoked by the social evaluation given by their peers who interacted with them previously. Results demonstrated that the TMS-activated DLPFC has a greater beneficial effect during distraction, whereas the activated VLPFC has a greater beneficial effect during reappraisal. This result investigated the direct experience of social pain and extended previous findings on empathy-related responses to affective pictures while also controlling for confounding factors such as empathic concern. Therefore, we are now confident in the double dissociation proposal of the DLPFC and VLPFC in distraction and reappraisal.

The VLPFC-Engaged Voluntary Emotion Regulation: Combined TMS-fMRI Evidence for the Neural Circuit of Cognitive Reappraisal.

A clear understanding of the neural circuit underlying emotion regulation (ER) is important for both basic and translational research. However, a lack of evidence based on combined neuroimaging and neuromodulation techniques calls into question (1) whether the change of prefrontal-subcortical activity intrinsically and causally contributes to the ER effect; and (2) whether the prefrontal control system directly modulates the subcortical affective system. Accordingly, we combined fMRI recordings with transcranial magnetic stimulation (TMS) to map the causal connections between the PFC and subcortical affective structures (amygdala and insula). A total of 117 human adult participants (57 males and 60 females) were included in the study. The results revealed that TMS-induced ventrolateral PFC (VLPFC) facilitation led to enhanced activity in the VLPFC and ventromedial PFC (VMPFC) as well as attenuated activity in the amygdala and insula during reappraisal but not during nonreappraisal (i.e., baseline). Moreover, the activated VLPFC intensified the prefrontal-subcortical couplings via the VMPFC during reappraisal only. This study provides combined TMS-fMRI evidence that downregulating negative emotion involves the prefrontal control system suppressing the subcortical affective system, with the VMPFC serving as a crucial hub within the VLPFC-subcortical network, suggesting an indirect pathway model of the ER circuit. Our findings outline potential protocols for improving ER ability by intensifying the VLPFC-VMPFC coupling in patients with mood and anxiety disorders.SIGNIFICANCE STATEMENT Using fMRI to examine the TMS effect, we uncovered that the opposite neural changes in prefrontal (enhanced) and subcortical (attenuated) regions are not a byproduct of emotion regulation (ER); instead, this prefrontal-subcortical activity per se causally contributes to the ER effect. Furthermore, using TMS to amplify the neural changes within the ER circuit, the "bridge" role of the VMPFC is highlighted under the reappraisal versus nonreappraisal contrast. This "perturb-and-measure" approach overcomes the correlational nature of fMRI data, helping us to identify brain regions that causally support reappraisal (the VLPFC and VMPFC) and those that are modulated by reappraisal (the amygdala and insula). The uncovered ER circuit is important for understanding the neural systems underlying reappraisal and valuable for translational research.

The role of ventrolateral prefrontal cortex on voluntary emotion regulation of social pain.

The right ventrolateral prefrontal cortex (rVLPFC) is highly engaged in emotion regulation of social pain. However, there is still lack of both inhibition and excitement evidence to prove the causal relationship between this brain region and voluntary emotion regulation. This study used high-frequency (10 Hz) and low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) to separately activate or inhibit the rVLPFC in two groups of participants. We recorded participants' emotion ratings as well as their social attitude and prosocial behaviors following emotion regulation. Also, we used eye tracker to record the changes of pupil diameter to measure emotional feelings objectively. A total of 108 healthy participants were randomly assigned to the activated, inhibitory or sham rTMS groups. They were required to accomplish three sequential tasks: the emotion regulation (cognitive reappraisal) task, the favorability rating task, and the donation task. Results show that the rVLPFC-inhibitory group reported more negative emotions and showed larger pupil diameter while the rVLPFC-activated group showed less negative emotions and reduced pupil diameter during emotion regulation (both compared with the sham rTMS group). In addition, the activated group gave more positive social evaluation to peers and donated more money to a public welfare activity than the rVLPFC-inhibitory group, among which the change of social attitude was mediated by regulated emotion. Taken together, these findings reveal that the rVLPFC plays a causal role in voluntary emotion regulation of social pain and can be a potential brain target in treating deficits of emotion regulation in psychiatric disorders.

Different Roles of the Left and Right Ventrolateral Prefrontal Cortex in Cognitive Reappraisal: An Online Transcranial Magnetic Stimulation Study.

The ventrolateral prefrontal cortex (VLPFC) plays a pivotal role in cognitive reappraisal. Previous studies suggested a functional asymmetry of the bilateral VLPFC, but the evidence is still insufficient during cognitive reappraisal. In this study, we conducted an online single-pulse transcranial magnetic stimulation (spTMS) to investigate the causal and distinct roles of the left and right VLPFC in reappraisal. Participants were instructed to reappraise (down-regulate) or attend to pictures depicting social exclusion scenarios while the spTMS was applied over the left or right VLPFC of the participants' brains. The results showed that spTMS of either the left or the right VLPFC would increase reappraisal difficulty. Meanwhile, the outcome of reappraisal (measured by self-reported negative feelings) significantly deteriorated when the right (but not the left) VLPFC was temporally interrupted by spTMS, while the verbal fluency during oral reporting of the reappraisal strategy was significantly reduced when the left VLPFC was interrupted by spTMS. Taken together, these findings provide causal evidence for the involvement of left and right VLPFC with distinct roles: while the left VLPFC is responsible for the linguistic especially semantic process of generating and selecting appraisals according to the goal of emotion regulation, the right VLPFC plays a critical role in inhibiting inappropriate negative emotions and thoughts generated by the effective scenarios. These findings deepen our understanding of the neurocognitive mechanism of emotion regulation.

Aberrant social feedback processing and its impact on memory, social evaluation, and decision-making among individuals with depressive symptoms.

BACKGROUND: Depression is associated with aberrant social feedback processing. However, little is known about the impact of these deficits on individuals' memory, social evaluation, and social decision-making. METHODS: We examined event-related potentials (ERPs) during the processing of social feedback with different emotional valences and intensities, among individuals with high and low depressive symptoms. After three days, participants performed a recall test, along with social evaluation and money allocation. RESULTS: Compared with the control group, participants with depressive symptoms showed larger occipital P1 and parietal P3 amplitudes to negative social feedback, as well as larger frontal feedback-related negativity toward highly positive social feedback; this indicates toward altered attentional allocation, encoding, and anticipation in social feedback processing. After three days of social feedback processing, individuals in the depressive symptom group recalled negative social feedback better and gave less positive evaluations and allocated less money to the senders of highly negative social feedback compared with control group participants. Notably, ERPs predicted subsequent memory, social evaluation, and decision-making, suggesting a significant impact of aberrant social feedback processing on social cognition and behaviors in depression. LIMITATIONS: Individuals with depressive symptoms rather than patients with depressive disorders were recruited and therefore caution is needed in applying the findings to clinical populations. CONCLUSIONS: Individuals with depressive symptoms exhibit negative bias in anticipation, attentional allocation, and encoding processes during social feedback processing, which further influences their memory, social evaluation, and social decision-making in the long run. These aberrant biases should be targeted to prevent the development of major depressive disorders.

ISIEA: An image database of social inclusion and exclusion in young Asian adults.

Human beings have a fundamental need to belong. Evaluating and dealing with social exclusion and social inclusion events, which represent negative and positive social interactions, respectively, are closely linked to our physical and mental health. In addition to traditional paradigms that simulate scenarios of social interaction, images are utilized as effective visual stimuli for research on socio-emotional processing and regulation. Since the current mainstream emotional image database lacks social stimuli based on a specific social context, we introduced an open-access image database of social inclusion/exclusion in young Asian adults (ISIEA). This database contains a set of 164 images depicting social interaction scenarios under three categories of social contexts (social exclusion, social neutral, and social inclusion). All images were normatively rated on valence, arousal, inclusion score, and vicarious feeling by 150 participants in Study 1. We additionally examined the relationships between image ratings and the potential factors influencing ratings. The importance of facial expression and social context in the image rating of ISIEA was examined in Study 2. We believe that this database allows researchers to select appropriate materials for socially related studies and to flexibly conduct experimental control.

Forgetting positive social feedback is difficult: ERP evidence in a directed forgetting paradigm.

Voluntary forgetting of unwanted memories is an adaptive cognitive function. However, it remains unknown how voluntary forgetting of unwanted social feedback may influence subsequent memories and evaluations, and what the underlying neurocognitive processes are. Here, we presented participants with peer photos together with feedback indicating social acceptance or rejection, followed by "remember" or "forget" instructive cues, while electroencephalograms were recorded during the experiment. We examined the Directed Forgetting (DF) effect in a recognition memory test, and tested participants' explicit and implicit attitudes toward the peers using a social evaluation task and an affect misattribution procedure (AMP). Both the memory test and the AMP were examined immediately and 3 days after the DF task so to estimate both the instant and the long-term effects of memory control. Behaviorally, immediate memory test showed smaller DF effect for positive than negative social feedback, which suggests that forgetting positive social feedback was more difficult than forgetting negative social feedback. Regarding the ERP results, although participants showed comparable frontal N2 amplitudes (reflecting inhibitory control efforts) following the instruction of forgetting positive and negative social feedback, positive feedback elicited larger late positive potential (LPP) amplitudes than negative feedback during initial encoding phase, suggesting an encoding bias for positive self-relevant information. Intriguingly, voluntary efforts to forget negative social feedback enhanced people's explicit and implicit evaluations toward the feedback senders. These findings provide new evidence for the adaptive function of memory control, which broadens the influence of voluntary forgetting in the context of social interaction and social evaluation.

The VLPFC versus the DLPFC in Downregulating Social Pain Using Reappraisal and Distraction Strategies.

The dorsolateral prefrontal cortex (DLPFC) and ventrolateral PFC (VLPFC) are both crucial structures involved in voluntary emotional regulation. However, it remains unclear whether the functions of these two cortical regions that are involved in emotional regulation, which are usually active in non-social situations, could be generalized to the regulation of social pain as well. This study employed transcranial magnetic stimulation (TMS) to examine the causal relationship between the DLPFC/VLPFC and the emotional regulation of social pain via distraction and reappraisal. Ninety human participants (45 males and 45 females) initially underwent either active (DLPFC/VLPFC, n = 30/30) or sham (vertex, n = 30) TMS sessions. Participants were then instructed to use both distraction and reappraisal strategies to downregulate any negative emotions evoked by social exclusion pictures. Convergent results of the subjective emotional rating and electrophysiological indices demonstrated that: (1) both the DLPFC and VLPFC highly facilitate the downregulation of affective responses caused by social exclusion, revealing a causal role of these lateral PFCs in voluntary emotional regulation of both non-social and social pain; and (2) these two cortical regions showed relative functional specificity for distraction (DLPFC) and reappraisal (VLPFC) strategies, which helps to refine the cortical targeting of therapeutic protocols. In addition, the TMS effect was sustainable for at least 1 h, showcasing the potential feasibility of using this method in clinical practice. Together, these findings provide cognitive and neural evidence for the targeting of the VLPFC and/or the DLPFC to improve emotional regulation abilities, especially in social contexts.SIGNIFICANCE STATEMENT This study aimed to examine the role of the dorsolateral prefrontal cortex (DLPFC) and ventrolateral PFC (VLPFC) in emotional regulation, particularly in response to social pain through the use of distraction and reappraisal strategies, as this is a relatively underexplored area of inquiry. This study makes a significant contribution to the literature because our results provide novel empirical information on the role of these cortical structures in the processing of negative emotions elicited within certain social contexts. As such, our findings have potential clinical implications, paving the way for future clinicians to be able to accurately target specific brain regions among patients struggling with impaired social cognition abilities, including those diagnosed with posttraumatic stress disorder, autism spectrum disorder, social anxiety disorder, and depression.

Negative Bias During Early Attentional Engagement in Major Depressive Disorder as Examined Using a Two-Stage Model: High Sensitivity to Sad but Bluntness to Happy Cues.

Negative attentional bias has been well established in depression. However, there is very limited knowledge about whether this depression-relevant negative bias exits during initial attentional allocation, as compared with the converging evidence for the negative bias during sustained attention engagement. This study used both behavioral and electrophysiological measures to examine the initial attention engagement in depressed patients influenced by mood-congruent and mood-incongruent emotions. The dot-probe task was performed with a 100-ms exposure time of the emotional cues (emotional and neutral face pairs). The behavioral results showed that the patients responded faster following valid compared with invalid sad facial cues. Electrophysiological indexes in the frame of the two-stage model of attentional modulation by emotions provided cognitive mechanisms in distinct attention engagement stages: (1) the patients exhibited reduced P1 amplitudes following validly than invalidly happy cues than did the healthy controls, indicating a positive attenuation at an early stage of automatic attention orientation; and (2) the patients exhibited enhanced whereas the controls showed reduced P3 amplitudes following validly than invalidly sad cues, suggesting a mood-congruent negative potentiation in depression at the later stage of top-down voluntary control of attention. Depressed patients show a negative bias in early attentional allocation, reflected by preferred engagement with mood-congruent and diminished engagement with positive emotional cues/stimuli.

Neural correlates of negative expectancy and impaired social feedback processing in social anxiety.

Social anxiety has been associated with abnormalities in cognitive processing in the literature, manifesting as various cognitive biases. To what extent these biases interrupt social interactions remains largely unclear. This study used the Social Judgment Paradigm that could separate the expectation and experience stages of social feedback processing. Event-related potentials (ERPs) in these two stages were recorded to detect the effect of social anxiety that might not be reflected by behavioral data. Participants were divided into two groups according to their social anxiety level. Participants in the high social anxiety (HSA) group were more likely to predict that they would be socially rejected by peers than did their low social anxiety (LSA) counterparts (i.e. the control group). Compared to the ERP data of the LSA group, the HSA group showed: (a) a larger P1 component to social cues (peer faces) prior to social feedback presentation, possibly indicating an attention bias; (b) a difference in feedback-related negativity amplitude between unexpected social acceptance and unexpected social rejection, possibly indicating an expectancy bias; and (c) a diminished sensitivity of the P3 amplitude to social feedback valence (be accepted/be rejected), possibly indicating an experience bias. These results could help understand the cognitive mechanisms that comprise and maintain social anxiety.

Trait Anxiety Attenuates Response Inhibition: Evidence From an ERP Study Using the Go/NoGo Task.

Neuropsychology and cognitive neuroscience have shown that anxious individuals have deficits in response inhibition. However, existing knowledge about the influence of trait anxiety on response inhibition is still inconsistent. The aim of this study was to investigate response inhibition between groups with high trait anxiety (HTA) and low trait anxiety (LTA). Here, we used event-related potential (ERP) indexes as biomarkers to examine the effect of trait anxiety on response inhibition using the Go/NoGo task. Behavioral results indicated that the HTA group made significantly lower accuracy than did the LTA group in the NoGo condition but not the Go condition. Meanwhile, the HTA group needed significantly longer overall response time (RT) than the LTA group did. ERP analyses revealed that the HTA group had smaller and later frontal NoGo-N2 as well as larger and later parietal NoGo-P3 compared to the LTA group. The two response inhibition-related ERP components are distinct neurophysiological indexes that, first, the NoGo-N2 is a component involved in the motor plan prior to the motor execution inhibitory process. Second, the NoGo-P3 reflects later monitoring and evaluation of the inhibition process. Accordingly, the current ERP findings suggest that HTA individuals' response inhibition deficits are the consequence of abnormal premotor inhibition control and inefficient evaluation and monitoring. In addition, we also found that the peak amplitude of NoGo-N2 and NoGo-P3 were significantly correlated with the State-Trait Anxiety Inventory (STAI) scores after correction for multiple comparisons. To sum up, these results support the notion that trait anxious individuals have response inhibition deficits in the Go/NoGo task.